DESCRIPTION(provided by applicant): Schizophrenics have high prevalence rates of cigarette smoking (58-88 percent) compared to the general population (-25 percent), and are often nicotine-dependent smokers who have considerable difficulty quitting smoking. Several factors may predispose these patients to cigarette smoking including alleviation of dysphoric mood states, improvements in extrapyramidal symptoms and deficits in information processing and neuropsychological function, as well as genetic factors that determine a vulnerability to both nicotine dependence and schizophrenia. Schizophrenic patients have deficits in cognitive function, including executive function (Wisconsin Card Sorting Test; WCST), verbal and spatial working memory Visuospatial Working Memory (VSWM)], response inhibition (Stroop Color-Word Test; SCWT), attention and concentration (Continuous Performance Test; CPT) and information processing {prepulse inhibition (PPI) of the startle response}. Preliminary evidence suggests that cigarette smoking can improve, and abstinence can worsen, cognitive function in schizophrenic patients. Nicotine withdrawal has been associated with reductions in central dopamine (DA) function in animal and human studies, and several of the above tasks are dependent, in part, on prefrontal cortical DA function. Our preliminary results suggest that smoking abstinence impairs visuospatial working memory (VSWM) in schizophrenic smokers, but improves VSWM in healthy smokers. However, the effects of cigarette smoking and abstinence on cognitive function in schizophrenic vs. healthy smokers have not been carefully evaluated. In the present studies, we will evaluate the effects of cigarette smoking and abstinence on cognitive tests known to be deficient in schizophrenic patients, including neuropsychological tests (WCST, SCWT, CPT, WSPT, VSWM) and PPI. After baseline testing, schizophrenic (n=25) and healthy control (n=25) smokers will undergo overnight smoking abstinence, followed by repeat testing, and then subsequent testing after resuming smoking. A group of schizophrenic (n=25) and healthy (n=25) non-smokers will serve as controls and complete the same sequence of testing. We will also assess the role of high-affinity nicotinic acetylcholine receptors (nAChRs), using pre-treatment with the nAChR antagonist mecamylamine (0.0, 5.0 and 10.0 mg/day), in mediating the effect of cigarette smoking on these cognitive assessments. Accordingly, these studies may provide data on the mechanisms by which cigarette smoking alters cognitive function in schizophrenic vs. control smokers, and suggest novel treatment approaches for both nicotine dependence and cognitive dysfunction in schizophrenic disorders.